RESUMO
Recent experimental data and clinical, genetic, and transcriptome evidence from patients converge to suggest a key role of interleukin-1ß (IL-1ß) in the pathogenesis of Kawasaki disease (KD). However, the molecular mechanisms involved in the development of cardiovascular lesions during KD vasculitis are still unknown. Here, we investigated intestinal barrier function in KD vasculitis and observed evidence of intestinal permeability and elevated circulating secretory immunoglobulin A (sIgA) in KD patients, as well as elevated sIgA and IgA deposition in vascular tissues in a mouse model of KD vasculitis. Targeting intestinal permeability corrected gut permeability, prevented IgA deposition and ameliorated cardiovascular pathology in the mouse model. Using genetic and pharmacologic inhibition of IL-1ß signaling, we demonstrate that IL-1ß lies upstream of disrupted intestinal barrier function, subsequent IgA vasculitis development, and cardiac inflammation. Targeting mucosal barrier dysfunction and the IL-1ß pathway may also be applicable to other IgA-related diseases, including IgA vasculitis and IgA nephropathy.
Assuntos
Doenças Cardiovasculares/imunologia , Imunoglobulina A/imunologia , Inflamação/imunologia , Intestinos/imunologia , Animais , Modelos Animais de Doenças , Humanos , Interleucina-1beta/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Linfonodos Mucocutâneos/imunologia , Permeabilidade , Transdução de Sinais/imunologia , Vasculite/imunologiaRESUMO
Glomerulonephritis (GN) is a group of inflammatory diseases and an important cause of morbidity and mortality worldwide. The initiation of the inflammatory process is quite different for each type of GN; however, each GN is characterized commonly and variably by acute inflammation with neutrophils and macrophages and crescent formation, leading to glomerular death. Toll-like receptor (TLR) 7 is a sensor for self-RNA and implicated in the pathogenesis of human and murine GN. Here, we show that TLR7 exacerbates glomerular injury in nephrotoxic serum nephritis (NTN), a murine model of severe crescentic GN. TLR7-/- mice were resistant to NTN, although TLR7-/- mice manifested comparable immune-complex deposition to wild-type mice without significant defects in humoral immunity, suggesting that endogenous TLR7 ligands accelerate glomerular injury. TLR7 was expressed exclusively in macrophages in glomeruli in GN but not in glomerular resident cells or neutrophils. Furthermore, we discovered that epidermal growth factor receptor (EGFR), a receptor-type tyrosine kinase, is essential for TLR7 signaling in macrophages. Mechanistically, EGFR physically interacted with TLR7 upon TLR7 stimulation, and EGFR inhibitor completely blocked the phosphorylation of TLR7 tyrosine residue(s). EGFR inhibitor attenuated glomerular damage in wild-type mice, and no additional glomerular protective effects by EGFR inhibitor were observed in TLR7-/- mice. Finally, mice lacking EGFR in macrophages were resistant to NTN. This study clearly demonstrated that EGFR-dependent TLR7 signaling in macrophages is essential for glomerular injury in crescentic GN.
Assuntos
Fator de Crescimento Epidérmico , Glomerulonefrite , Camundongos , Humanos , Animais , Receptor 7 Toll-Like , Receptores ErbB , Macrófagos/metabolismoRESUMO
BACKGROUND: Machine Learning has been increasingly used in the medical field, including managing patients undergoing hemodialysis. The random forest classifier is a Machine Learning method that can generate high accuracy and interpretability in the data analysis of various diseases. We attempted to apply Machine Learning to adjust dry weight, the appropriate volume status of patients undergoing hemodialysis, which requires a complex decision-making process considering multiple indicators and the patient's physical conditions. METHODS: All medical data and 69,375 dialysis records of 314 Asian patients undergoing hemodialysis at a single dialysis center in Japan between July 2018 and April 2020 were collected from the electronic medical record system. Using the random forest classifier, we developed models to predict the probabilities of adjusting the dry weight at each dialysis session. RESULTS: The areas under the receiver-operating-characteristic curves of the models for adjusting the dry weight upward and downward were 0.70 and 0.74, respectively. The average probability of upward adjustment of the dry weight had sharp a peak around the actual change over time, while the average probability of downward adjustment of the dry weight formed a gradual peak. Feature importance analysis revealed that median blood pressure decline was a strong predictor for adjusting the dry weight upward. In contrast, elevated serum levels of C-reactive protein and hypoalbuminemia were important indicators for adjusting the dry weight downward. CONCLUSIONS: The random forest classifier should provide a helpful guide to predict the optimal changes to the dry weight with relative accuracy and may be useful in clinical practice.
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Asiático , Alterações do Peso Corporal , Aprendizado de Máquina , Diálise Renal , Humanos , Pressão Sanguínea , Peso Corporal , Algoritmo Florestas Aleatórias , JapãoRESUMO
While angiotensin-converting enzyme (ACE) regulates blood pressure by producing angiotensin II as part of the renin-angiotensin system, we recently reported that elevated ACE in neutrophils promotes an effective immune response and increases resistance to infection. Here, we investigate if such neutrophils protect against renal injury in immune complex (IC)-mediated crescentic glomerulonephritis (GN) through complement. Nephrotoxic serum nephritis (NTN) was induced in wild-type and NeuACE mice that overexpress ACE in neutrophils. Glomerular injury of NTN in NeuACE mice was attenuated with much less proteinuria, milder histological injury, and reduced IC deposits, but presented with more glomerular neutrophils in the early stage of the disease. There were no significant defects in T and B cell functions in NeuACE mice. NeuACE neutrophils exhibited enhanced IC uptake with elevated surface expression of FcγRII/III and complement receptor CR1/2. IC uptake in neutrophils was enhanced by NeuACE serum containing elevated complement C3b. Given no significant complement activation by ACE, this suggests that neutrophil ACE indirectly preactivates C3 and that the C3b-CR1/2 axis and elevated FcγRII/III play a central role in IC elimination by neutrophils, resulting in reduced glomerular injury. The present study identified a novel renoprotective role of ACE in glomerulonephritis; elevated neutrophilic ACE promotes elimination of locally formed ICs in glomeruli via C3b-CR1/2 and FcγRII/III, ameliorating glomerular injury.NEW & NOTEWORTHY We studied immune complex (IC)-mediated crescentic glomerulonephritis in NeuACE mice that overexpress ACE only in neutrophils. Such mice show no significant defects in humoral immunity but strongly resist nephrotoxic serum nephritis (less proteinuria, milder histological damage, reduced IC deposits, and more glomerular neutrophils). NeuACE neutrophils enhanced IC uptake via increased surface expression of CR1/2 and FcgRII/III, as well as elevated serum complement C3b. These results suggest neutrophil ACE as a novel approach to reducing glomerulonephritis.
Assuntos
Glomerulonefrite , Nefrite , Angiotensina II/metabolismo , Animais , Complexo Antígeno-Anticorpo/metabolismo , Complemento C3b/metabolismo , Glomerulonefrite/metabolismo , Camundongos , Nefrite/metabolismo , Neutrófilos/metabolismo , Proteinúria/metabolismoRESUMO
Chronic kidney disease (CKD) causes hyperphosphatemia and secondary hyperparathyroidism, leading to several disorders of bone metabolism. Although high concentrations of extracellular inorganic phosphate (Pi) inhibit osteoclastogenesis, the molecular mechanism of this effect has not been fully understood. In the present study, therefore, we examined the effect of Pi on the differentiation of the osteoclast precursor RAW-D cells. Treatment with the receptor activator of nuclear factor-kappa B ligand induced the differentiation of RAW-D cells (osteoclastogenesis). However, Pi significantly weakened this effect, assessed by the tartrate-resistant acid phosphatase (TRAP) activity and the number of TRAP-positive multinucleated cells. Pi also reduced the expressions of nuclear factor of activated T-cell (NFAT) c1 and dendritic cell-specific transmembrane protein (DC-STAMP). Interestingly, the Pi-induced reduction of DC-STAMP gene promoter activity was lost when the activator protein 1 (AP-1) binding site was mutated. Since Pi strongly inhibited the expression of c-Fos which is the component of AP-1, the Pi-induced reduction of DC-STAMP expression was proposed to be mediated by the absence of c-Fos. These results suggested that hyperphosphatemia in the patients with CKD suppresses bone resorption by inhibiting osteoclastogenesis, and this impairs the regulation of bone metabolism.
Assuntos
Fusão Celular , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Osteoclastos/metabolismo , Osteogênese/fisiologia , Fosfatos/administração & dosagem , Ligante RANK/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Relação Dose-Resposta a Droga , Camundongos , Osteoclastos/citologiaRESUMO
BACKGROUND: Hemodialysis patients are at increased risk for bone fracture and sarcopenia. There is close interplay between skeletal muscle and bone. However, it is still unclear whether lower skeletal muscle mass increases the risk for bone fracture. STUDY DESIGN: Cross-sectional study and prospective longitudinal cohort study. SETTING & PARTICIPANTS: An independent cohort of 78 hemodialysis patients in the cross-sectional study and 3,030 prevalent patients undergoing maintenance hemodialysis prospectively followed up for 4 years. PREDICTOR: Skeletal muscle mass measured by bioelectrical impedance analysis (BIA) and modified creatinine index, an estimate of skeletal muscle mass based on age, sex, Kt/V for urea, and serum creatinine level. OUTCOMES: Bone fracture at any site. RESULTS: In the cross-sectional study, modified creatinine index was significantly correlated with skeletal muscle mass measured by BIA. During a median follow-up of 3.9 years, 140 patients had bone fracture. When patients were divided into sex-specific quartiles based on modified creatinine index, risk for bone fracture estimated by a Fine-Gray proportional subdistribution hazards model with all-cause death as a competing risk was significantly higher in the lower modified creatinine index quartiles (Q1 and Q2) compared to the highest modified creatinine index quartile (Q4) as the reference value in both sexes (multivariable-adjusted HRs for men were 7.81 [95% CI, 2.63-23.26], 5.48 [95% CI, 2.08-14.40], 2.24 [95% CI, 0.72-7.00], and 1.00 [P for trend < 0.001], and for women were 4.44 [95% CI, 1.50-13.11], 2.33 [95% CI, 0.86-6.31], 1.96 [95% CI, 0.82-4.65], and 1.00 [P for trend = 0.007] for Q1, Q2, Q3, and Q4, respectively). LIMITATIONS: One-time assessment of modified creatinine index; no data for residual kidney function and fracture sites and causes. CONCLUSIONS: Modified creatinine index was correlated with skeletal muscle mass measured by BIA. Lower modified creatinine index was associated with increased risk for bone fracture in male and female hemodialysis patients.
Assuntos
Creatinina/sangue , Fraturas Ósseas/epidemiologia , Diálise Renal , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/terapia , Biomarcadores/sangue , Estudos de Coortes , Estudos Transversais , Impedância Elétrica , Feminino , Fraturas Ósseas/etiologia , Humanos , Estudos Longitudinais , Masculino , Músculo Esquelético/anatomia & histologia , Estudos Prospectivos , Diálise Renal/efeitos adversos , Medição de RiscoRESUMO
Although dietary phosphate restriction is important for treating hyperphosphatemia in patients with chronic kidney disease, it remains unclear whether a low-protein diet (LPD), which contains low phosphate, has beneficial effects on malnutrition, inflammation, and vascular calcification. The effects of LPD on inflammation, malnutrition, and vascular calcification were therefore assessed in rats. Rats were fed a normal diet or diets containing 0.3% adenine and low/normal protein and low/high phosphate. After 6 wk, serum and urinary biochemical parameters, systemic inflammation, and vascular calcification were examined. The protective effect of fetuin-A and albumin were assessed in cultured vascular smooth muscle cells. Rats fed the diet containing 0.3% adenine developed severe azotemia. LPD in rats fed high phosphate induced malnutrition (decreases in body weight, food intake, serum albumin and fetuin-A levels, and urinary creatinine excretion) and systemic inflammation (increases in serum tumor necrosis factor-α and urinary oxidative stress marker). LPD decreased the serum fetuin-A level and fetuin-A synthesis in the liver and increased serum calcium-phosphate precipitates. A high-phosphate diet increased aortic calcium content, which was enhanced by LPD. Reduced fetal calf serum in the medium of cultured vascular smooth muscle cells enhanced phosphate-induced formation of calcium-phosphate precipitates in the media and calcification of vascular smooth muscle cells, both of which were prevented by fetuin-A administration. Our results suggest that phosphate restriction by restricting dietary protein promotes vascular calcification by lowering the systemic fetuin-A level and increasing serum calcium-phosphate precipitates and induces inflammation and malnutrition in uremic rats fed a high-phosphate diet.
Assuntos
Dieta com Restrição de Proteínas , Hiperfosfatemia/complicações , Uremia/complicações , Calcificação Vascular/etiologia , alfa-2-Glicoproteína-HS/metabolismo , Albuminas/farmacologia , Animais , Fosfatos de Cálcio/metabolismo , Células Cultivadas , Hiperfosfatemia/metabolismo , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Fósforo na Dieta/farmacologia , Desnutrição Proteico-Calórica/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo , Uremia/metabolismo , Calcificação Vascular/metabolismo , alfa-2-Glicoproteína-HS/deficiência , alfa-2-Glicoproteína-HS/farmacologiaRESUMO
Vascular calcification (VC) is a critical complication in patients with chronic kidney disease (CKD). The effects of spironolactone (SPL), a mineralocorticoid receptor (MR) antagonist, on VC have not been fully investigated in CKD. The present in vivo study determined the protective effects of SPL on VC in CKD rats. Rats were divided into a control group and four groups of rats with adenine-induced CKD. Three groups were treated with 0, 50, and 100 mg·kg(-1)·day(-1) SPL for 8 wk, and one group was treated with 100 mg·kg(-1)·day(-1) SPL for the last 2 wk of the 8-wk treatment period. After 8 wk, CKD rats developed azotemia and hyperphosphatemia, with increases in the expression of serum and glucocorticoid-regulated kinase-1 and sodium-phosphate cotransporter, in inflammation and oxidative stress level, in osteogenic signaling and apoptosis, and in aortic calcification, compared with control rats. SPL dose dependently decreased these changes in the aortas, concomitant with improvements in renal inflammation, tubulointerstitial nephritis, and kidney function. SPL neither lowered blood pressure level nor induced hyperkalemia. Treatment of CKD rats for the last 2 wk with 100 mg·kg(-1)·day(-1) SPL attenuated VC compared with CKD rats with the same degree of kidney function and hyperphosphatemia. In conclusion, SPL dose dependently inhibits the progression of VC by suppressing MR signaling, local inflammation, osteogenic transition, and apoptosis in the aortas of CKD rats.
Assuntos
Aorta Abdominal/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Receptores de Mineralocorticoides/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Espironolactona/farmacologia , Túnica Média/efeitos dos fármacos , Uremia/tratamento farmacológico , Calcificação Vascular/prevenção & controle , Adenina , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Doenças da Aorta/sangue , Doenças da Aorta/induzido quimicamente , Doenças da Aorta/patologia , Doenças da Aorta/fisiopatologia , Apoptose/efeitos dos fármacos , Biomarcadores/sangue , Modelos Animais de Doenças , Progressão da Doença , Relação Dose-Resposta a Droga , Humanos , Hiperfosfatemia/sangue , Hiperfosfatemia/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Masculino , Osteogênese/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de Mineralocorticoides/metabolismo , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Túnica Média/metabolismo , Túnica Média/patologia , Uremia/sangue , Uremia/induzido quimicamente , Uremia/patologia , Uremia/fisiopatologia , Calcificação Vascular/sangue , Calcificação Vascular/induzido quimicamente , Calcificação Vascular/patologia , Calcificação Vascular/fisiopatologiaRESUMO
Hyperphosphatemia contributes to increased cardiovascular mortality through vascular calcification (VC) in patients with chronic kidney disease (CKD). Malnutrition and inflammation are also closely linked to an increased risk of cardiovascular death in CKD. However, the effects of Pi overload on inflammation and malnutrition remain to be elucidated. The aim of the present study was to investigate the effects of dietary Pi loading on the interactions among inflammation, malnutrition, and VC in CKD. We used control rats fed normal diets and adenine-induced CKD rats fed diets with different Pi concentrations ranging from 0.3% to 1.2% for 8 wk. CKD rats showed dietary Pi concentration-dependent increases in serum and tissue levels of TNF-α and urinary and tissue levels of oxidative stress markers and developed malnutrition (decrease in body weight, serum albumin, and urinary creatinine excretion), VC, and premature death without affecting kidney function. Treatment with 6% lanthanum carbonate blunted almost all changes induced by Pi overload. Regression analysis showed that serum Pi levels closely correlated with the extent of inflammation, malnutrition, and VC. Also, in cultured human vascular smooth muscle cells, high-Pi medium directly increased the expression of TNF-α in advance of the increase in osteochondrogenic markers. Our data suggest that dietary Pi overload induces systemic inflammation and malnutrition, accompanied by VC and premature death in CKD, and that inhibition of Pi loading through dietary or pharmacological interventions or anti-inflammatory therapy may be a promising treatment for the prevention of malnutrition-inflammation-atherosclerosis syndrome.
Assuntos
Inflamação/induzido quimicamente , Desnutrição/induzido quimicamente , Fosfatos/efeitos adversos , Fosfatos/farmacologia , Insuficiência Renal Crônica/metabolismo , Uremia/metabolismo , Calcificação Vascular/induzido quimicamente , Proteínas de Fase Aguda/metabolismo , Adenina/efeitos adversos , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Inflamação/metabolismo , Masculino , Desnutrição/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismo , Uremia/fisiopatologia , Calcificação Vascular/metabolismoRESUMO
Glyphosate is a widely used herbicide that is generally considered safe; however, acute kidney injury (AKI) caused by glyphosate ingestion can be severe and require hemodialysis. We present a unique case of a 68-year-old Japanese man who developed AKI after accidental ingestion of glyphosate and required hemodialysis. Based on the clinical presentation and findings, the patient was diagnosed with renal AKI with severe tubulointerstitial damage. However, the precise pathogenesis of the tubulointerstitial damage remained unclear. An elevated beta-2 microglobulin level discovered by the urinalysis during admission raised the suspicion of tubulointerstitial nephritis caused by glyphosate. Gallium scintigraphy revealed accumulation in both kidneys. A renal biopsy revealed acute tubulointerstitial nephritis rather than acute tubular necrosis, which is commonly observed with glyphosate-induced renal injury. After initiating steroid therapy, his kidney function gradually improved and he was weaned from hemodialysis. This report is the first to describe glyphosate-induced acute tubulointerstitial nephritis that was successfully treated with immunosuppressive therapy. Furthermore, this report highlights the importance of steroid therapy for cases of persistent kidney injury after the discontinuation of agents associated with acute tubulointerstitial nephritis.
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BACKGROUND: In recent years, the emergence of multiplex technology that can simultaneously measure multiple anti-islet autoantibodies has become particularly valuable for the staging and early diagnosis of immune-mediated type 1 diabetes (T1D). While it has been established that 20%-30% of T1D patients suffer from autoimmune thyroid disease (AITD), there is limited available data regarding the presence of anti-islet autoantibodies in AITD patients. Among commercially available anti-islet autoantibodies, glutamic acid decarboxylase 65 autoantibodies (GADAs) are often the first marker measured in general clinical practice. AIM: To investigate the frequency of anti-islet autoantibodies in AITD patients. METHODS: Our study involved four hundred ninety-five AITD patients, categorized into three distinct groups: AITD with T1D (n = 18), AITD with phenotypic type 2 diabetes (T2D) (n = 81), and AITD without diabetes (n = 396), and the enzyme-linked immunosorbent assay (ELISA) was employed to determine the frequencies of 3 Screen Islet Cell Autoantibody (3 Screen ICA), GADA, insulinoma-associated antigen-2 autoantibodies (IA-2As), and zinc transporter 8 autoantibodies (ZnT8As) within these groups. RESULTS: The frequency of 3 Screen ICA in AITD patients with T1D, T2D, and those without diabetes were 88.9%, 6.2%, and 5.1%, respectively, with no significant difference seen between the latter two groups. Notably, the frequency of 3 Screen ICA was 11.1% higher in AITD patients with T1D, 1.3% higher in AITD patients with T2D, and 1.1% higher in AITD patients without diabetes compared to GADA, respectively. Furthermore, 12.5%, 20.0%, and 20.0% of the 3 Screen ICA-positive patients were negative for GADA. Additionally, 1.3% of the AITD patients who tested negative for 3 Screen ICA in both the AITD with T2D and non-diabetic AITD groups were found to be positive for individual autoantibodies. Among the 3 Screen ICA-positive patients, there was a significantly higher proportion of individuals with multiple autoantibodies in AITD patients with T1D compared to those without diabetes (37.5% vs 5.0%, P < 0.05). However, this proportion was similar to that in AITD patients with T2D (20.0%). Nevertheless, there was no significant difference in 3 Screen ICA titers between AITD patients with T1D and those without diabetes (436.8 ± 66.4 vs 308.1 ± 66.4 index). Additionally, no significant difference in 3 Screen ICA titers was observed between Graves' disease and Hashimoto's thyroiditis in any of the groups. CONCLUSION: Our findings reveal that some AITD patients without diabetes exhibit 3 Screen ICA titers comparable to those in AITD patients with T1D. Thus, 3 Screen ICA outperforms GADA in identifying latent anti-islet autoantibody-positive individuals among AITD patients.
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Infection-related glomerulonephritis (IRGN) is one of the most common causes of acute kidney injury (AKI). Positive glomerular staining of the nephritis-associated plasmin receptor (NAPlr) has been reported as a useful biomarker of IRGN. Although the infection can provoke acute tubulointerstitial nephritis (AIN), there are few reports of positive staining for NAPlr with AIN. We report a case of methicillin-sensitive Staphylococcus aureus (MSSA) infection-related nephritis complicated with AIN, which showed positive staining for tubulointerstitial NAPlr. The patient developed AKI and nephrotic syndrome during an intraperitoneal MSSA infection. A diagnosis of IRGN complicated by infection-related acute tubulointerstitial nephritis (IRAIN) was made based on glomerular endocapillary proliferation with tubulointerstitial infiltrating cells and tubular atrophy. Tubulointerstitial infiltrating cells were positive for NAPlr staining and plasmin activity. Treatment of the infection by antibiotics and drainage did not improve the AKI, but steroid administration improved that. NAPlr evaluation is a helpful tool for identifying causes of AIN during infection.
Assuntos
Injúria Renal Aguda , Glomerulonefrite por IGA , Glomerulonefrite , Nefrite Intersticial , Nefrite , Infecções Estafilocócicas , Humanos , Glomerulonefrite/diagnóstico , Glomerulonefrite por IGA/complicações , Nefrite/complicações , Nefrite Intersticial/complicações , Nefrite Intersticial/diagnóstico , Nefrite Intersticial/tratamento farmacológico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/complicações , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/tratamento farmacológico , Imunoglobulina ARESUMO
Kidneys have the capacity for intrinsic repair, preserving kidney architecture with return to a basal state after tubular injury. When injury is overwhelming or repetitive, however, that capacity is exceeded and incomplete repair results in fibrotic tissue replacing normal kidney parenchyma. Loss of nephrons correlates with reduced kidney function, which defines chronic kidney disease (CKD) and confers substantial morbidity and mortality to the worldwide population. Despite the identification of pathways involved in intrinsic repair, limited treatments for CKD exist, partly because of the limited throughput and predictivity of animal studies. Here, we showed that kidney organoids can model the transition from intrinsic to incomplete repair. Single-nuclear RNA sequencing of kidney organoids after cisplatin exposure identified 159 differentially expressed genes and 29 signal pathways in tubular cells undergoing intrinsic repair. Homology-directed repair (HDR) genes including Fanconi anemia complementation group D2 (FANCD2) and RAD51 recombinase (RAD51) were transiently up-regulated during intrinsic repair but were down-regulated in incomplete repair. Single cellular transcriptomics in mouse models of obstructive and hemodynamic kidney injury and human kidney samples of immune-mediated injury validated HDR gene up-regulation during tubular repair. Kidney biopsy samples with tubular injury and varying degrees of fibrosis confirmed loss of FANCD2 during incomplete repair. Last, we performed targeted drug screening that identified the DNA ligase IV inhibitor, SCR7, as a therapeutic candidate that rescued FANCD2/RAD51-mediated repair to prevent the progression of CKD in the cisplatin-induced organoid injury model. Our findings demonstrate the translational utility of kidney organoids to identify pathologic pathways and potential therapies.
Assuntos
Organoides , Insuficiência Renal Crônica , Animais , Cisplatino/farmacologia , Reparo do DNA , Recombinação Homóloga , Rim , CamundongosRESUMO
Podocyte injury is involved in the onset and progression of various kidney diseases. We previously demonstrated that the transcription factor, old astrocyte specifically induced substance (OASIS) in myofibroblasts, contributes to kidney fibrosis, as a novel role of OASIS in the kidneys. Importantly, we found that OASIS is also expressed in podocytes; however, the pathophysiological significance of OASIS in podocytes remains unknown. Upon lipopolysaccharide (LPS) treatment, there is an increase in OASIS in murine podocytes. Enhanced serum creatinine levels and tubular injury, but not albuminuria and podocyte injury, are attenuated upon podocyte-restricted OASIS knockout in LPS-treated mice, as well as diabetic mice. The protective effects of podocyte-specific OASIS deficiency on tubular injury are mediated by protein kinase C iota (PRKCI/PKCι), which is negatively regulated by OASIS in podocytes. Furthermore, podocyte-restricted OASIS transgenic mice show tubular injury and tubulointerstitial fibrosis, with severe albuminuria and podocyte degeneration. Finally, there is an increase in OASIS-positive podocytes in the glomeruli of patients with minimal change nephrotic syndrome and diabetic nephropathy. Taken together, OASIS in podocytes contributes to podocyte and/or tubular injury, in part through decreased PRKCI. The induction of OASIS in podocytes is a critical event for the disturbance of kidney homeostasis.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Podócitos , Albuminúria/genética , Albuminúria/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/metabolismo , Fibrose , Homeostase , Rim/metabolismo , Lipopolissacarídeos/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Regulação para CimaRESUMO
Background: Nephropathy in patients with thymic diseases such as thymoma and myasthenia gravis (MG) is rare and has been described mostly as isolated case reports. Here we evaluate a series of kidney biopsies from patients with thymoma and/or MG from a single institution in order to better define the spectrum and relative frequencies of thymic disease-associated nephropathies. Methods: We conducted a retrospective case series study of 32 462 native kidney biopsies from January 2005 through December 2019 at Cedars-Sinai Medical Center, Los Angeles, CA, USA. Results: Twenty-four biopsy specimens (0.07%) from patients with a history of thymoma and/or MG were identified. Two patients had repeat biopsies. The most common pathologic diagnosis that could be immunologically attributed to thymic disease was minimal change disease (MCD; 45%), followed by tubulointerstitial nephritis (TIN; 14%), immune complex (IC)-mediated glomerulonephritis (9%), membranous nephropathy (5%) and immunoglobulin A (IgA) nephropathy (5%). Interestingly, 50% of the MCD and 67% of TIN cases concomitantly showed mild IgG-dominant IC deposition in mesangial areas and/or in tubular basement membranes. In the two patients with repeat biopsies, mild mesangial IC deposition developed in the MCD patient but disappeared in the TIN patient with the second biopsy. Pathologic diagnoses unlikely related to the underlying thymic disease were diabetic glomerulosclerosis (9%), acute tubular necrosis (9%) and monoclonal Ig deposition disease (5%). Conclusions: Thymic disease is associated with a wide spectrum of kidney diseases affecting the glomerular and tubulointerstitial compartments, often with low-grade IC deposition. These findings suggest a role of immunologic dysregulation in the pathogenesis of thymic disease-associated nephropathy.
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Sendai virus is a member of the family Paramyxoviridae, and an enveloped virus with a negative-stranded RNA genome. Sendai virus is not pathogenic to humans, but for mice and can cause pneumonia in mice. Easy and efficient techniques for propagating Sendai virus are required for studying virus replication, virus-induced innate- and adaptive-immunity, Sendai-virus-based virotherapy and IgA nephropathy. Here, we describe a protocol for Sendai virus propagation using chicken eggs. This traditional protocol enables us to generate a large amount of virus enough for animal experiments as well as cell culture experiments in a relatively inexpensive way.
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Sendai virus (SeV) is an enveloped, single-stranded RNA virus of the family Paramyxoviridae. SeV is a useful tool to study its infectious pathomechanism in immunology and the pathomechanism of a murine model of IgA nephropathy. Virus quantification is essential not only to determine the original viral titers for an appropriate application, but also to measure the viral titers in samples from the harvests from experiments. There are mainly a couple of units/titers for Sendai viral quantification: plaque-forming units (PFU) and hemagglutination (HA) titer. Of these, we here describe a protocol for Sendai virus plaque assay to provide PFU using LLC-MK2 cells (a rhesus monkey kidney cell lines) and Guinea pig red blood cells. This traditional protocol enables us to determine Sendai virus PFU in viral stock as well as samples from your experiments.
RESUMO
The use of phosphate (P)-binders allows hemodialysis patients to take in more protein and thus may maintain a good nutritional status. Protein-energy-malnutrition increases the risk of infection-related death. The association between use of P-binders and the relative risks of infection-related death remains unknown in hemodialysis patients. A total of 2926 hemodialysis patients registered to the Q-Cohort Study was followed up for 4-years. The association between use of P-binders and the risks for infection-related and all-cause mortality were estimated by Cox proportional hazards risk model with multiple adjustments by conventional and propensity-score based approaches. During the follow-up period, 106 patients and 492 patients died of infection and any cause, respectively. Cox proportional hazards models with multivariable adjustments including nutritional confounders showed that the incidence of infection-related death was significantly lower in patients with P-binders use compared with those without (hazard ratio [95% confidence interval] for infection-related mortality 0.63 [0.40-0.99]). The results remained significant even after applying four different propensity score-based analyses. Notably, use of P-binders was associated with a lower risk of all-cause mortality. Further studies including randomized controlled clinical trials and observational studies analyzed by an instrumental variable model will provide more robust evidences for the associations observed in our study.
Assuntos
Doenças Transmissíveis/etiologia , Doenças Transmissíveis/mortalidade , Fosfatos/farmacologia , Diálise Renal/efeitos adversos , Diálise Renal/mortalidade , Idoso , Estudos de Coortes , Doenças Transmissíveis/sangue , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Fatores de RiscoRESUMO
As fibroblast growth factor 23 (FGF23) has been shown to induce cardiovascular disease directly in patients with chronic kidney disease, identification of factors and treatments that can modulate serum FGF23 (sFGF23) level is clinically important. This retrospective longitudinal study investigated factors that modulate sFGF23 in 49 patients who underwent peritoneal dialysis (PD). sFGF23 ratio (sFGF23 at 18 months/baseline sFGF23) was used as an indicator of changes in sFGF23 level. Total phosphate elimination was the sum of both renal phosphate excretion and dialysate phosphate elimination. In multivariate analysis, log sFGF23 ratio was associated negatively with total phosphate elimination and the use of cinacalcet at baseline, and positively with the use of vitamin D receptor activators at baseline, even after adjusting for potential confounding factors. Our study indicates that maintaining phosphate elimination can prevent increased sFGF23, thereby preventing cardiovascular events in patients who undergo PD.
Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Diálise Peritoneal , Fosfatos/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/terapia , Biomarcadores/metabolismo , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
AIMS: Clinical studies have shown that very low protein diet (VLPD) has negative effects on long-term survival. It remains unclear why VLPD induces premature death. The present study determined the underlying mechanism whereby VLPD exerts its harmful effects on uremic rats. MAIN METHODS: Rats were divided into four groups and fed a normal diet or diets containing 0.3% adenine and low/normal protein with high/low phosphate. After 6 weeks, body weight, urinary biochemistry (creatinine and phosphate), serum biochemical parameters (urea, creatinine, fibroblast growth factor 23, albumin, and fetuin-A), systemic inflammatory markers (serum tumor necrosis factor-alpha and urinary 8-hydroxy-2'-deoxyguanosine), calcium content in the aorta, and serum calcium-phosphate precipitates were evaluated. Hepatic mRNA levels were also determined. KEY FINDINGS: Rats fed the diet containing 0.3% adenine developed severe azotemia. Rats fed VLPD developed malnutrition (decreases in body weight, serum albumin and fetuin-A levels, and urinary creatinine excretion) and systemic inflammation (increases in serum tumor necrosis factor-α and urinary 8-hydroxy-2'-deoxyguanosine) independent of phosphate status. VLPD decreased the serum fetuin-A level and hepatic fetuin-A synthesis and increased serum calcium-phosphate precipitates, a marker of calciprotein particle. A high-phosphate diet induced arterial medial calcification, which was enhanced by VLPD. Serum calcium-phosphate precipitate levels were correlated with the degree of inflammation, malnutrition, and aortic calcium content. Dietary phosphate restriction prevented VLPD-enhanced vascular calcification, but could not halt inflammation and malnutrition induced by VLPD. SIGNIFICANCE: VLPD enhances inflammation, malnutrition, and vascular calcification in uremic rats, among which only vascular calcification is prevented by dietary phosphate restriction.